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Publication numberUS5780062 A
Publication typeGrant
Application numberUS 08/553,460
PCT numberPCT/SE1995/001302
Publication dateJul 14, 1998
Filing dateNov 3, 1995
Priority dateNov 9, 1994
Fee statusPaid
Also published asCA2203512A1, CN1165478A, DE69525639D1, DE69525639T2, EP0788350A1, EP0788350B1, WO1996014833A1
Publication number08553460, 553460, PCT/1995/1302, PCT/SE/1995/001302, PCT/SE/1995/01302, PCT/SE/95/001302, PCT/SE/95/01302, PCT/SE1995/001302, PCT/SE1995/01302, PCT/SE1995001302, PCT/SE199501302, PCT/SE95/001302, PCT/SE95/01302, PCT/SE95001302, PCT/SE9501302, US 5780062 A, US 5780062A, US-A-5780062, US5780062 A, US5780062A
InventorsSylvan Frank, Jan-Erik Lofroth, Levon Bostanian
Original AssigneeThe Ohio State University Research Foundation
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Small particle formation
US 5780062 A
Abstract
The present invention is concerned with the formation of small particles of organic compounds by precipitating said organic compounds in an aqueous medium containing polymer/amphiphile complexes. The process is preferably used to prepare a readily soluble pharmaceutically active compound.
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Claims(7)
We claim:
1. A process for preparing small particles comprising an organic compound, the solubility of which is greater in a water-miscible first solvent than in a second solvent which is aqueous, which process comprises the following steps:
(i) dissolving said organic compound in the water-miscible first solvent,
(ii) preparing a solution of polymer and an amphiphile in the aqueous second solvent and in which second solvent the organic compound is substantially insoluble whereby a polymer/amphiphile complex is formed, and
(iii) mixing the solutions from steps (i) and (ii) so as to cause precipitation of an aggregate comprising the organic compound and the polymer/amphiphile complex.
2. A process according to claim 1, wherein the polymer and amphiphile present in the solution produced according to step (ii) are at concentrations below the critical concentration at which free micelles begin to form.
3. A process according to claim 1 wherein flocculation of the precipitated aggregate is achieved by the addition of an electrolyte, and thereafter separation of the aggregate is achieved by means of centrifugation so that aggregates of less than 2 μm in size are separated out.
4. A process according to any one of the preceding claims wherein the polymer and the amphiphile are mixed in solution, interact and are precipitated by the addition of a hydrophobic organic compound.
5. A process according to claim 4 wherein the compound is pharmaceutically active.
6. A process as claimed in claim 5 wherein the pharmaceutically active compound is an antihyperlipidemic agent.
7. A process according to claim 6 in which the polymer is a pharmaceutically acceptable adjuvant.
Description

The present invention is concerned with the formation of small particles of organic compounds upon precipitation when a solution of such an organic compound in a water-miscible solvent is added to an aqueous medium containing polymer and an amphiphilic compound (surfactant or lipid) at a concentration at which polymer/amphiphile complexes are formed. At said concentrations, the system is a solution below the critical concentration at which free micelles are formed. Upon addition of the organic compound, the compound interacts with the polymer/amphiphile complexes, thus increasing their hydrophobicity and leading to precipitation of organic compound/polymer/amphiphile aggregates.

According to the present invention, a small particle refers to a particle size of less than 2 μm.

The object of the invention is to provide a process for the formation of small particles of organic compounds, especially pharmaceutically active compounds, where such process does not involve emulsification or water-immisicible solvents.

The process is preferably used to prepare a readily soluble pharmaceutically active compound.

BACKGROUND OF THE INVENTION

From a pharmaceutical point of view, the smaller the particle size of a relatively insoluble drug, the grater is its rate of solution and as a rule, the greater is its bioavailability (J. H. Fincher, J. Pharm. Sci., 57, 1825 (1968)). To this end, small particles are conventionally formed by mechanical subdivision of bulk matter or by aggregation of small molecules or ions (D. J. Shaw, "Introduction to Colloid and Surface Chemistry", 3rd Ed., Butterworths, London, 1980, Chapter 1).

Studies of polymer/amphiphile systems in aqueous media have shown that interactions of polymers with charged amphiphiles occur in different stages. Ionic polymers and charged amphiphiles of opposite charge precipitate accordingly by electrostatic interactions. On the other hand, interactions between non-ionic polymers and amphiphiles occur in three stages. In the most dilute solutions, very little physical biding occurs. At concentrations of amphiphile higher than the critical micelle concentration, true micelles form. However, between these two concentrations, complexation or binding of polymer to amphiphile occurs (M. L. Fishman and F. R. Eirich, J. Phys. Chem., 75(20), 3135-40 (1971)). Small polymer/amphiphile aggregates or sub-micelles are thus formed. The presence of the amphiphile introduces an effective attraction between different polymer molecules since the formed aggregates could involve more than one polymer molecule. This attraction, together with the binding of the amphiphile to the polymer would lead to an increase in the hydrophobicity of the polymer. If the aggregate is sufficiently hydrophobic it will precipitate. The addition of a polar water-soluble compound (e.g. NaCl) to a polymer/amphiphile system will further enhance the precipitation of the polymer/amphiphile aggregates because there will be an increased difference in polarity between the solvent and the polymer/amphiphile aggregates and because the polar compound will tend to decrease the number of water molecules available for the hydration of the polymer/amphiphile aggregates. Also, precipitation occurs on increasing the temperature of systems containing polymers for which solubility is inversely related to temperature, such as cellulosic derivatives. The cloud point of hydroxypropylmethylcellulose (HPMC) has been shown to be lowered by addition of amphiphiles, the effect being more pronounced in the presence of salt (J. E. Lofroth, L. Johansson, A. C. Norman, and K. Wettstrom, Progr. Colloid. Polym. Sci., 84, 73-77 (1991)).

On the other hand, if a hydrophobic compound is added, it will tend to interact with the polymer/amphiphile aggregates, thus increasing the hydrophobicity of these polymer/amphiphile aggregates and facilitating their precipitation.

SUMMARY OF THE INVENTION

A method has now been found which surprisingly involves the formation of small particles, the growth of which is limited by the adsorption and/or concentration of polymer/amphiphile aggregates at the solid/liquid interface.

Thus, the invention concerns a process for preparing small particles comprising an organic compound, the solubility of which is greater in a water-miscible first solvent than in a second solvent which is aqueous, which process comprises the following steps:

(i) dissolving said organic compound in the water-miscible first solvent,

(ii) preparing a solution of a polymer and an amphiphile in the aqueous second solvent and in which second solvent the organic compound is substantially insoluble whereby a polymer/amphiphile complex is formed, and

(iii) mixing the solutions from steps (i) and (ii) so as to cause precipitation of an aggregate comprising the organic compound and the polymer/amphiphile complex.

The new method for the formation of small particles of an organic compound comprises:

1) Dissolving said compound in a first solvent which is water-miscible and in which said compound is soluble.

2) Preparing a solution of polymer and amphiphile in a second solvent which is aqueous and in which the compound for which small particles are desired is more or less insoluble, preferably at concentrations below the critical concentration at which free micelles begin to form. The concentrations of polymer and amphiphile are such that they interact, but the critical micelle concentration of the amphiphile is not reached. The hydrophobicity of the polymer is thus increased to a desired degree at which no precipitation occurs. Precipitation of the polymer could also be prevented by temperature control in the cases where solubility of the polymer is a function of temperature.

3) Mixing the solutions from steps (1) and (2) while stirring. The organic compound interacts with the polymer/amphiphile complexes, thus increasing their hydrophobicity, and precipitation of drug/polymer/amphiphile aggregates occurs.

4) The formed particles are then separated, preferably by flocculation and collected by suitable means.

An organic compound for use in the process of this invention is any organic chemical entity whose solubility decreases from one solvent to another. This organic compound might be a pharmaceutically active compound from various groups such as, but not limited to: antihyperlipidemics, antimicrobials, e.g. sulfadiazine; non-steroidal anti-inflammatories, e.g., indomethacin; antihypercholesteremic agents, e.g., probucol; and steroidal compounds, e.g., dexamethasone. Or the organic compound might be from the group used as adjuvants or excipients in pharmaceutical preparations and cosmetics, such as, but not limited to, preservatives, e.g., propylparaben.

The first solvent according to the present invention is a solvent or mixture of solvents in which the organic compound of interest is relatively soluble and which is miscible with the second solvent. Examples of such solvents include, but are not limited to: methanol, ethanol, isopropanol, acetone, dimethylformamide, and acetonitrile.

The second solvent according to the present invention is water or an aqueous solution containing one or more of various additives, such as, but not limited to:

1. polymers, such as dextrans; polyethylene glucols; polyvinylpyrrolidone; cellulosic derivatives, e.g., methylcellulose and hydroxypropylmethylcellulose; gelatin; and carrageenan.

2. salts, such as monovalent ions, e.g., sodium chloride; divalent ions, e.g., sodium sulfate and calcium chloride; and trivalent ions, e.g., aluminum chloride.

3. surfactants such as nonionics, e.g., sorbitan fatty acid esters and their polyoxyethylene derivatives; anionics, e.g., sodium dodecylsulfate; and cationics, e.g., cetyltrimethylammonium bromide.

4. viscosity enhancing agents, such as, hydrophilic colloids, e.g., gelatin, acacia and tragacanth.

5. cosolvents, such as glycerol, propylene glycol, methanol, ethanol and isopropanol.

A polymer according to the invention, the solution of which is prepared in the second solvent, is meant to be a wide variety of organic chemical entities of relatively high molecular weight, such as, but not limited to:

1. vinyl derivatives, e.g., polyvinylpyrrolidone.

2. cellulose derivatives, e.g., methylcellulose and hydroxypropylmethylcellulose.

3. polyethylene glycols, e.g., polyethylene glycol 6,000 and polyethylene glycol 10,000.

An amphiphile according to the invention is a compound, the molecules of which consist of two parts, one of which is hydrophilic and the other of which is hydrophobic in nature. These compounds include, but are not limited to:

1. nonionics, e.g., cholesterol, lecithin, sorbitan fatty acid esters and their polyoxyethylene derivatives.

2. anionics, such as, alkylsulfates, e.g., sodium dodecylsulfate; and bile salts, e.g., sodium cholate and sodium taurocholate.

3. cationics, e.g., cetyltrimethylammonium bromide and benzalkonium chloride.

The concentration of the organic compound in the first solvent can be as low as 0.01% by weight and as high as, but not limited to, the saturation concentration of the organic compound in the first solvent, including concentrations which form supersaturated solutions within the range of temperatures up to the boiling point of the first solvent.

The concentration of the polymer can be ranging from 0.01% to 50% by weight in the second solvent, preferably 0.01% to 10%.

The concentration of the amphiphile can be ranging from 0.001% to 50% by weight in the second solvent, preferably 0.001% to 5%.

Flocculation can be achieved by various modes, such as

1. addition of an electrolyte, such as, but not limited to, sodium sulfate, sodium phosphate and potassium phosphate.

2. temperature change.

3. addition of a high molecular weight polymer (bridging flocculation).

Collection of the small particles can be achieved by various methods, such as, but not limited to:

1. centrifugation and ultracentrifugation.

2. filtration.

3. reverse osmosis followed by evaporation.

4. evaporation of the solvent by heating and/or vacuum.

5. freeze-drying.

6. spray-drying.

7. fluidized-bed drying.

8. any combination of the above.

DETAILED DESCRIPTION OF THE INVENTION

According to one embodiment of the invention, the process comprises the following steps:

1) Dissolving a pharmaceutically active compound, such as an antihyperlipidemic agent, in a first solvent which is water-miscible;

2) Dissolving polyvinylpyrrolidone and sodium dodecylsulfate in a second solvent which is aqueous such as water and in which the active compound is more or less insoluble. The concentrations of both polyvinylpyrrolidone and sodium dodecylsulfate are such that the system is below the critical concentration at which free micelles form and precipitation of the polymer/amphiphile complex has not occurred.

3) Adding the solution obtained from step (1) to that prepared in step (2) while keeping the latter under constant agitation. Precipitation occurs and results in a suspension of drug/polymer/amphiphile small particles.

4) The small particles thus obtained are flocculated by the addition of an aqueous solution of an electrolyte, such as potassium phosphate.

5) The suspension is centrifuged and washed twice with water, centrifuged, redispersed in water and then freeze-dried.

The process of forming small particles according to the invention is illustrated by the following example:

EXAMPLE

A solution consisting of 1 g of probucol (a lipid lowering drug) and 12 ml of absolute ethanol was added to a solution consisting of 2 g polyvinylpyrrolidone (M. W. 360.000), 0.1 g sodium dodecylsulfate and 50 ml water while stirring at 1.200 rpm with a magnetic stirrer. This procedure resulted in a white suspension of small particles comprising probucol. The small particles were then flocculated by adding a potassium phosphate solution. The flocculated small particles were separated by centrifugation, washed twice with water, redispersed by sonication and then freeze-dried. The process was monitored by observation of samples in the optical microscope. The final freeze-dried product was observed by electron microscopy; agglomerates of small particles of less than 2 μm were observed.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US4606940 *Dec 21, 1984Aug 19, 1986The Ohio State University Research FoundationSmall particle formation and encapsulation
US4826689 *May 17, 1985May 2, 1989University Of RochesterMethod for making uniformly sized particles from water-insoluble organic compounds
EP0169618A2 *May 21, 1985Jan 29, 1986STERILIZATION TECHNICAL SERVICES, Inc.Method for making uniformly sized particles from water-insoluble organic compounds
EP0486959B1 *Nov 15, 1991Aug 28, 1996Vectorpharma International S.P.A.Pharmaceutical composition of microparticles with controlled release and process of preparing it
GB2122085A * Title not available
JPH0249720A * Title not available
WO1986003676A1 *Dec 17, 1985Jul 3, 1986The Ohio State University Research FoundationSmall particle formation and encapsulation
WO1990015593A1 *Jun 15, 1990Dec 27, 1990Ytkemiska InstitutetA process for the preparation of drug particles
Non-Patent Citations
Reference
1 *Derwent Abstract Accession No. 93 14549, Bostonian et al. Formation of Small Particles of a Relativly Insoluble Drug, Pharm. Res. 9, No. 10, Suppl., S224, 1992.
2Derwent Abstract Accession No. 93-14549, Bostonian et al. "Formation of Small Particles of a Relativly Insoluble Drug," Pharm. Res. 9, No. 10, Suppl., S224, 1992.
3 *Derwent Abstract Accession No. 95 06706, Bostonian et al., Characterization of Small Particles of Probucol, Pharm. Res. 11, No. 10, Suppl., S326, 1994.
4Derwent Abstract Accession No. 95-06706, Bostonian et al., "Characterization of Small Particles of Probucol," Pharm. Res. 11, No. 10, Suppl., S326, 1994.
5Fincher, J.H. "Particle Size of Drugs and Its Relationship to Absorption and Activity" J. Pharm. Sciences 57(11): 1825-1835, 1968.
6 *Fincher, J.H. Particle Size of Drugs and Its Relationship to Absorption and Activity J. Pharm. Sciences 57(11): 1825 1835, 1968.
7Lofroth et al. "Interactions between surfactants and polymers. I:HPMC," Prog. Colloid Polym. Sci., 84:73-77 (1991).
8 *Lofroth et al. Interactions between surfactants and polymers. I:HPMC, Prog. Colloid Polym. Sci., 84:73 77 (1991).
9M. L. Fishman et al., "Interactions of Aqueous Poly (N-vinylpyrrolidone) with Sodium Dodecyl Sulfate," J. Phys. Chem., vol. 75, No. 20, 1971, p. 3135.
10 *M. L. Fishman et al., Interactions of Aqueous Poly (N vinylpyrrolidone) with Sodium Dodecyl Sulfate, J. Phys. Chem., vol. 75, No. 20, 1971, p. 3135.
11Shaw, D.J. "Introduction to Colloid and Surface Chemistry" 3rd Ed. Butterworths Pub. pp. 1-18, 1980.
12 *Shaw, D.J. Introduction to Colloid and Surface Chemistry 3rd Ed. Butterworths Pub. pp. 1 18, 1980.
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US6623761Dec 22, 2000Sep 23, 2003Hassan Emadeldin M.Method of making nanoparticles of substantially water insoluble materials
US6835396Jun 26, 2002Dec 28, 2004Baxter International Inc.Preparation of submicron sized nanoparticles via dispersion lyophilization
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US6977085Oct 19, 2001Dec 20, 2005Baxter International Inc.Method for preparing submicron suspensions with polymorph control
US7029700Jan 12, 2001Apr 18, 2006Brown University Research FoundationMicronized freeze-dried particles
US7037528Jun 5, 2001May 2, 2006Baxter International Inc.Microprecipitation method for preparing submicron suspensions
US7112340Oct 11, 2002Sep 26, 2006Baxter International Inc.Compositions of and method for preparing stable particles in a frozen aqueous matrix
US7193084Aug 5, 2002Mar 20, 2007Baxter International Inc.Polymorphic form of itraconazole
US7473693Feb 2, 2004Jan 6, 2009Astrazeneca AbStable dispersion of solid particles comprising a water-insoluble pyrazine compound
US7511079Mar 22, 2004Mar 31, 2009Baxter International Inc.Methods and apparatuses for the comminution and stabilization of small particles
US7780989Jul 14, 2003Aug 24, 2010Astrazeneca AbProcess for the preparation of crystalline nano-particle dispersions
US7833549Jan 19, 2001Nov 16, 2010Mannkind CorporationDry powder formulations of antihistamine for nasal administration
US7833550Aug 21, 2007Nov 16, 2010Mannkind CorporationDry powder formulations of antihistamine for nasal administration
US8067032Nov 7, 2003Nov 29, 2011Baxter International Inc.Method for preparing submicron particles of antineoplastic agents
US8101274Jun 11, 2007Jan 24, 2012Spedden Richard HSolid state membranes with surface-embedded glycosylated amphiphilic molecules and micelles formed therefrom
US8263131Mar 30, 2009Sep 11, 2012Baxter International Inc.Method for treating infectious organisms normally considered to be resistant to an antimicrobial drug
US8309129Apr 21, 2008Nov 13, 2012Bend Research, Inc.Nanoparticles comprising a drug, ethylcellulose, and a bile salt
US8333959Jun 9, 2005Dec 18, 2012Baxter International Inc.Ex-vivo application of solid microparticulate therapeutic agents
US8426467May 22, 2007Apr 23, 2013Baxter International Inc.Colored esmolol concentrate
US8518431Jul 6, 2012Aug 27, 2013Bioactive Surgical, Inc.Stem cell capture and immobilization coatings for medical devices and implants
US8524829Jun 17, 2008Sep 3, 2013Brown University Research FoundationMethods for micronization of hydrophobic drugs
US8530463Nov 6, 2008Sep 10, 2013Hale Biopharma Ventures LlcMultimodal particulate formulations
US8617467Sep 22, 2004Dec 31, 2013Baxter International Inc.High-pressure sterilization to terminally sterilize pharmaceutical preparations and medical products
US8703204Apr 23, 2008Apr 22, 2014Bend Research, Inc.Nanoparticles comprising a cholesteryl ester transfer protein inhibitor and anon-ionizable polymer
US8722091Aug 17, 2004May 13, 2014Baxter International Inc.Preparation of submicron sized nanoparticles via dispersion lyophilization
US8722736May 22, 2007May 13, 2014Baxter International Inc.Multi-dose concentrate esmolol with benzyl alcohol
US8889168Aug 7, 2009Nov 18, 2014Bioactive Surgical Inc.Stem cell capture and immobilization coatings for medical devices and implants
US8895546Jun 13, 2012Nov 25, 2014Hale Biopharma Ventures, LlcAdministration of benzodiazepine compositions
US8974827May 26, 2008Mar 10, 2015Bend Research, Inc.Nanoparticles comprising a non-ionizable cellulosic polymer and an amphiphilic non-ionizable block copolymer
US8986736Apr 19, 2006Mar 24, 2015Baxter International Inc.Method for delivering particulate drugs to tissues
US9044381Jun 15, 2004Jun 2, 2015Baxter International Inc.Method for delivering drugs to the brain
US9233078Dec 5, 2008Jan 12, 2016Bend Research, Inc.Nanoparticles comprising a non-ionizable polymer and an Amine-functionalized methacrylate copolymer
US9364443Mar 5, 2009Jun 14, 2016Baxter International, Inc.Compositions and methods for drug delivery
US9545384May 26, 2008Jan 17, 2017Bend Research, Inc.Nanoparticles comprising drug, a non-ionizable cellulosic polymer and tocopheryl polyethylene glocol succinate
US20020009418 *Jan 19, 2001Jan 24, 2002Steiner Solomon S.Dry powder formulations of antihistamine for nasal administration
US20020127278 *Jun 5, 2001Sep 12, 2002Kipp James E.Microprecipitation method for preparing submicron suspensions
US20020168402 *Jun 5, 2001Nov 14, 2002Kipp James E.Microprecipitation method for preparing submicron suspensions
US20030003155 *Sep 17, 2001Jan 2, 2003Kipp James E.Microprecipitation method for preparing submicron suspensions
US20030031719 *May 30, 2002Feb 13, 2003Kipp James E.Method for preparing submicron particle suspensions
US20030044433 *Oct 19, 2001Mar 6, 2003Jane WerlingMethod for preparing submicron suspensions with polymorph control
US20030059472 *Jun 26, 2002Mar 27, 2003Sean BrynjelsenPreparation of submicron sized nanoparticles via dispersion lyophilization
US20030077329 *Oct 11, 2002Apr 24, 2003Kipp James EComposition of and method for preparing stable particles in a frozen aqueous matrix
US20030082236 *Jan 12, 2001May 1, 2003Edith MathiowitzMicronized freeze-dried particles
US20030096013 *Sep 17, 2002May 22, 2003Jane WerlingPreparation of submicron sized particles with polymorph control
US20030100568 *Aug 5, 2002May 29, 2003Jane WerlingPolymorphic form of itraconazole
US20030170309 *Jun 17, 2002Sep 11, 2003Babcock Walter C.Pharmaceutical compositions containing polymer and drug assemblies
US20030206959 *Dec 12, 2001Nov 6, 2003Kipp James E.Method for preparing submicron particle suspensions
US20030211160 *Jun 4, 2003Nov 13, 2003Patrice GuitardPharmaceutical compositions
US20040070093 *Aug 12, 2003Apr 15, 2004Brown University Research FoundationProcess for preparing microparticles through phase inversion phenomena
US20040256749 *Oct 29, 2003Dec 23, 2004Mahesh ChaubalProcess for production of essentially solvent-free small particles
US20040266890 *Mar 22, 2004Dec 30, 2004Kipp James E.Methods and apparatuses for the comminution and stabilization of small particles
US20050009908 *Aug 1, 2002Jan 13, 2005Hedberg Pia Margaretha CeciliaAqueous dispersion comprising stable nonoparticles of a water-insoluble active and an excipient like middle chain triglycerides (mct)
US20050048002 *Jun 15, 2004Mar 3, 2005Barrett RabinowMethod for delivering drugs to the brain
US20050100595 *Nov 30, 2004May 12, 2005Brown University Research FoundationMethods for micronization of hydrophobic drugs
US20050170002 *Feb 7, 2005Aug 4, 2005Kipp James E.Method for preparing submicron particle suspensions
US20050181059 *Sep 30, 2004Aug 18, 2005Spherics, Inc.Nanoparticulate therapeutic biologically active agents
US20050196416 *Jan 26, 2005Sep 8, 2005Kipp James E.Dispersions prepared by use of self-stabilizing agents
US20050202092 *Jul 14, 2003Sep 15, 2005Skantze Tommy U.Process for the preparation of crystalline nano-particle dispersions
US20050202094 *Jan 21, 2005Sep 15, 2005Werling Jane O.Nanosuspensions of anti-retroviral agents for increased central nervous system delivery
US20050244503 *May 19, 2004Nov 3, 2005Rabinow Barrett ESmall-particle pharmaceutical formulations of antiseizure and antidementia agents and immunosuppressive agents
US20050276861 *Jun 9, 2005Dec 15, 2005Kipp James EEx-vivo application of solid microparticulate therapeutic agents
US20060073199 *Sep 12, 2005Apr 6, 2006Mahesh ChaubalSurfactant systems for delivery of organic compounds
US20060115533 *Oct 21, 2005Jun 1, 2006Patrice GuitardPharmaceutical compositions
US20060122229 *Dec 18, 2003Jun 8, 2006Astrazeneca Ab4,5-diarylthiazole derivatives as cb-1 ligands
US20060122230 *Dec 18, 2003Jun 8, 2006Astrazeneca Ab1,5-Diaryl-pyrrole-3-carboxamide derivatives and their use as cannabinoid receptor modulators
US20060134146 *Feb 2, 2004Jun 22, 2006Astrazeneca AbStable dispersion of solid particles comprising a water-insoluble pyrazine compound
US20060135523 *Jun 16, 2004Jun 22, 2006Astrazeneca Ab2-substituted 5,6-diaryl-pyrazine derivatives as cb1 modulator
US20060141043 *Feb 2, 2004Jun 29, 2006Astrazeneca A BAqueous dispersion comprising stable nanoparticles of a water-insoluble thiazole derivative and excipients like middle chain triglycerides
US20060198893 *Feb 2, 2004Sep 7, 2006Astrazeneca AbAqueous dispersion comprising stable nanoparticles of a water-insoluble pyrrole carboxamide and excipient like middle chain triglycerides
US20060280430 *Apr 19, 2006Dec 14, 2006Rabinow Barrett EMethod for delivering particulate drugs to tissues
US20070081947 *Oct 19, 2004Apr 12, 2007Bayer Technology Service GmbhSolid active ingredient formulation
US20070093484 *Jun 16, 2004Apr 26, 2007Astrazeneca Ab3-Substituted 5,6-diaryl-pyrazine-2-carboxamide and -2-sulfonamide derivatives as cb1 modulators
US20070093505 *Jun 16, 2004Apr 26, 2007Astrazeneca Ab2,3-Substituted 5,6-diaryl-pyrazine derivatives as cb1 modulators
US20080171687 *Sep 16, 2005Jul 17, 2008Abraxis Bioscience, Inc.Compositions And Methods For The Preparation And Administration Of Poorly Water Soluble Drugs
US20080279784 *May 7, 2008Nov 13, 2008Questcor Pharmaceuticals, Inc.Nasal administration of benzodiazepines
US20080305348 *Jun 11, 2007Dec 11, 2008Spedden Richard HSolid State Membranes with Surface-Embedded Glycosylated Amphiphilic Molecules and Micelles Formed Therefrom
US20090130216 *Nov 6, 2008May 21, 2009Hale Biopharma VenturesMultimodal particulate formulations
US20090258865 *Mar 27, 2009Oct 15, 2009Hale Biopharma Ventures, LlcAdministration of benzodiazepine compositions
US20100086611 *Mar 30, 2009Apr 8, 2010Baxter International Inc.Method for Treating Infectious Organisms Normally Considered to be Resistant to an Antimicrobial Drug
US20100119603 *Apr 21, 2008May 13, 2010Warren Kenyon MillerNanoparticles comprising a drug,ethycellulose,and a bile salt
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US20100184946 *Jul 17, 2008Jul 22, 2010Van Boxtel Huibert AlbertusPreparation of Fine Particles
US20100190690 *Jun 11, 2008Jul 29, 2010Spedden Richard HBiomimetic particles and films for pathogen capture and other uses
US20100290983 *May 15, 2009Nov 18, 2010Baxter International Inc.Compositions and Methods for Drug Delivery
US20110166218 *Jun 17, 2008Jul 7, 2011Edith MathiowitzMethods for micronization of hydrophobic drugs
US20140199397 *Jun 8, 2012Jul 17, 2014Daniel LevinBenzoyl Peroxide Microparticle Process
CN100512798CDec 20, 2001Jul 15, 2009巴克斯特国际公司Method for preparing submicron particle suspensions
EP1423175A1 *Aug 8, 2002Jun 2, 2004Brown University Research FoundationMethods for micronization of hydrophobic drugs
EP1423175A4 *Aug 8, 2002Mar 28, 2007Univ Brown Res FoundMethods for micronization of hydrophobic drugs
WO2002055059A2 *Dec 20, 2001Jul 18, 2002Baxter IntMethod for preparing submicron particle suspensions
WO2002055059A3 *Dec 20, 2001Sep 6, 2002Baxter International Inc.Method for preparing submicron particle suspensions
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WO2005044221A3 *Oct 19, 2004Apr 6, 2006Peter BaurSolid active ingredient formulation
WO2009013466A1 *Jul 17, 2008Jan 29, 2009Fujifilm Manufacturing Europe B.V.Preparation of fine particles
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Classifications
U.S. Classification424/501, 424/489
International ClassificationA61K9/14, B01J13/10, A61K9/16
Cooperative ClassificationA61K9/1635, B01J13/10, A61K9/1694, A61K9/1617
European ClassificationA61K9/16H6B, A61K9/16P4, B01J13/10, A61K9/16H4
Legal Events
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Nov 27, 1995ASAssignment
Owner name: OHIO STATE UNIVERSITY RESEARCH FOUNDATION, THE, OH
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